RESUMEN
Clavulanic acid (CLAV) is a component of Augmentin® that preserves antibiotic efficacy by inhibiting ß-lactamase activity. It also enhances cellular glutamate uptake and is a potential CNS therapeutic. Because increased glutamate transmission in brain reward circuits facilitates methamphetamine (METH) locomotor activation and sensitization, we tested the hypothesis that CLAV inhibits acute and sensitized locomotor responses to METH in mice and investigated effects of CLAV on METH-induced changes in glutaminase, the major glutamate-producing enzyme in the brain. Acute METH (3 mg/kg) produced hyperlocomotion that was reduced by CLAV (20 mg/kg but not 10 mg/kg). Mice injected with METH (3 mg/kg) every other day for 9 d and then challenged with METH 27 d later displayed locomotor sensitization. CLAV (10 mg/kg), when injected 15 min before each METH injection during the 9-d exposure interval, blocked locomotor sensitization induced by METH challenge. In METH-sensitized mice, mRNA levels of both isoforms of glutaminase (GLS and GLS2) were altered in the nucleus accumbens compared to mice exposed to a single injection of METH (i.e., GLS decreased and GLS2 increased). CLAV normalized the METH-induced GLS deficit but not the increase in GLS2. In summary, CLAV reduced acute and sensitized locomotor responses to METH and normalized the METH-induced reduction of GLS gene expression in the NAC. Given that glutaminases belong to the ß-lactamase superfamily and CLAV is a ß-lactamase inhibitor, our data point toward studying glutaminase as a therapeutic target of CLAV.
Asunto(s)
Estimulantes del Sistema Nervioso Central , Ácido Clavulánico , Glutaminasa , Metanfetamina , Núcleo Accumbens , ARN Mensajero , Animales , Metanfetamina/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Glutaminasa/metabolismo , Masculino , Ácido Clavulánico/farmacología , ARN Mensajero/metabolismo , ARN Mensajero/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Ratones Endogámicos C57BL , Ratones , Locomoción/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Relación Dosis-Respuesta a DrogaRESUMEN
Energy drinks pose consumer and environmental risks. One of the few organisms suitable for investigating both risks are planarians, which display mammalian-like behavioral effects during drug exposure and reside in aquatic environments. We investigated effects of Monster Energy® (0.001 - 10%) on planarian behaviors using established assays. For acute exposure, only higher concentrations reduced motility (>1%) and caused stereotypies (>1%). Lower concentrations (0.1-1%) enhanced light avoidance, a measure of defensive responding. In place conditioning experiments conducted with low concentrations (0.0001%-0.1%), planarians avoided the energy drink-paired side. These results suggest that Monster Energy® causes aversive effects in aquatic life such as planarians.